Definitive Phase 1B and Phase 2B trials of a candidate blood stage malaria vaccine based on Plasmodium falciparum apical membrane antigen 1, or AMA-1, in combination with GlaxoSmithKline Biologicals'adjuvant AS02A, an immune boosting agent, will be conducted in children in Bandiagara, Mali, West Africa. This project is central to the overall program goal of developing a safe and effective malaria vaccine that prevents disease and death in African infants and children. Blood samples obtained in these clinical trials will be subject to the molecular and immunological analyses described in the Project 2 Research Plan. Those analyses will provide information on strain-specific vs. cross-reactive protection, duration of immune response, and the impact of natural boosting, all of which will inform further vaccine development efforts, including determining which components would be best to include in a multi-component vaccine. A pediatric Phase 1B study in Mali will compare three different doses of AMA-1/AS02A. The malaria vaccine or a comparator vaccine will be injected at 0, 1, and 2 months in a staggered, dose escalating fashion to evaluate safety of the vaccine and its ability to produce an immune response in children. Based on the results of this trial, the best vaccine dose level will be chosen for a Phase 2B study of AMA-1 efficacy. This Phase 2B double blind, controlled trial in children will determine if the malaria vaccine is safe, immunogenic and effective at preventing malaria disease and infection. The greatest public health goal for an effective malaria vaccine is to reduce disease and death in children, particularly in Africa. The proposed studies will evaluate the ability of the vaccine to mitigate malaria infection and disease and thus estimate its potential either alone or as a component of a multi-antigen malaria vaccine. If successful, this vaccine may be further developed as a stand-alone vaccine or combined with other protective malaria antigens and/or AMA-1 genotypes. A vaccine that provides protection against both malaria infection and malaria disease will benefit not only African children but also travelers to malaria endemic regions, providing a market to subsidize a vaccine for use in the malaria endemic world.